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Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5α... - 0 views

jcem.endojournals.org/...5907.short PCOS women lean 11-betaHSD1 5-alpha-reductase androgens testosterone insulin syndrome
shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    lean women with PCOS found to have reduced 11 beta-HSD1 and increased 5 alpha reductase activity.  This, in part, is associated with the elevated cortisol and androgens in these women.
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ScienceDirect.com - The Journal of Steroid Biochemistry and Molecular Biology - Progest... - 0 views

www.sciencedirect.com/...S0960076009001216 progesterone progestins breast cancer receptors PR
shared by Nathan Goodyear on 15 May 12 - No Cached
  • Nathan Goodyear on 15 May 12
     
    this study states that progesterone promotes breast growth and has implications of breast cancer.  However, this study looked at progestins not progesterone.  Studies have shown a reduction of breast cancer risk with progesterone and an increase with progestins.  It would have been nice to have looked at "progesterone" metabolites.  This study shows the flaw that many have: the intermix progesterone and progestins as if they are one in the same and they are clearly not
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Progesterone metabolites in breast cancer - 1 views

erc.endocrinology-journals.org/...717.full progesterone metabolism tumor tumorigenesis cancer risk growth hormone hormones 5-beta-pregnanediol 5-alpha-pregnanediol 4-pregnenediol 5-alpha reductase
shared by Nathan Goodyear on 20 Feb 12 - No Cached
  • P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
  • these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
  • only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
  • ...30 more annotations...
  • P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
  • 5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
  • These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
  • Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
  • The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
  • the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
  • In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
  • The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
  • he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
  • The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
  • altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
  • In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
  • Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
  • The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
  • 3αHP inhibited whereas 5αP-stimulated proliferation
  • Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
  • Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
  • αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
  • The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
  • he effects on proliferation and adhesion were not due to P, but due to the 5α-reduced metabolites
  • The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
  • separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
  • The studies thus provided the first demonstration of the existence of specific P metabolite receptors
  • the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
  • Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
  • In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
  • The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
  • current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
  • both testosterone and DHT inhibit cell growth more or less to the same extent
  • Note that 5α-reductase reaction is not reversible
  • Nathan Goodyear on 20 Feb 12
     
    Fantastic read on the effects of progesterone metabolism on tumor and cancer growth.  Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones.  This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
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The 4-Pregnene and 5α-Pregnane Progesterone Metabolites Formed in Nontumorous... - 0 views

cancerres.aacrjournals.org/...936.full progesterone metabolism cancer risk 4-pregnene 5alpha-pregnane
shared by Nathan Goodyear on 17 Feb 12 - No Cached
  • We report here the first evidence that tumorous breast tissue exhibits elevated 5α-reductase activity, which promotes significant increases in 5α-pregnanes, especially 5αP,4 whereas the normal (nontumorous) breast tissue produces more 4-pregnenes, especially 3αHP
  • 3αHP and other 4-pregnenes inhibit, whereas 5αP and other 5α-pregnanes stimulate, breast cell proliferation and detachment
  • it is evident that breast tissue can convert progesterone into two classes of metabolites: the δ-4-pregnenes (which retain the C4–5 double bond), and the 5α-reduced 21-carbon steroids (5α-pregnanes)
  • ...12 more annotations...
  • irreversible action of 5α-reductase
  • in normal (nontumorous) breast tissue, the 4-pregnene metabolites of progesterone greatly exceeded the 5α-pregnanes, whereas in tumorous tissue, 5α-pregnanes exceeded 4-pregnenes.
  • These differences in 5α-pregnane and 4-pregnene amounts were largely attributable to differences in 5αP and 3αHP production in tumorous and nontumorous tissues
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
  • These findings suggest greatly elevated 5α-reductase activity in tumorous, as compared with nontumorous, breast tissue.
  • progesterone metabolites that retain the C-4 double bond (i.e., the 4-pregnenes) exert an antiproliferative effect in the three cell lines that were tested, whereas the 5α-pregnanes stimulate breast cell line proliferation.
  • the degree of mitogenicity would be determined by the ratio of 5α-pregnanes:4-pregnenes. Tissues with a high 4-pregnene:5α-pregnane ratio would maintain a higher degree of normalcy, whereas those with a high 5α-pregnane:4-pregnene ratio would tend toward tumorigenicity
  • The observations that progesterone metabolites affect both ER-positive and ER-negative cells as well as tumorigenic (MCF-7) and nontumorigenic (MCF-10A) cells strengthen the argument that these factors may be endocrinologically relevant for all forms of breast cancer.
  • progesterone metabolites as the active endocrine/paracrine/autocrine factors
  • Estrogen-based therapies elicit responses in only one-third of all breast cancer patients, and most of these show relapse.
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
    • Nathan Goodyear
      Nathan Goodyear on 27 Jan 14
       
      Interesting that the effect of progesterone metabolites were found to be independent from ER status, age, and pre/post menopause
  • Nathan Goodyear on 17 Feb 12
     
    Different progesterone metabolites shown to have different tumor effects.  Implications are that, just as estrogen metabolism effects cancer risk, so does progesterone metabolism.
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Comparison of Sex Steroid Measurements in Men by Immunoassay versus Mass Spectroscopy a... - 0 views

www.ncbi.nlm.nih.gov/...PMC2636568 MS mass spectroscopy immunoassay hormone hormones measurement measurements bone mineral density
shared by Nathan Goodyear on 24 Jun 12 - No Cached
  • Nathan Goodyear on 24 Jun 12
     
    Mass Spectroscopy proves to be better test, specifically specificity, in men due to low Estradiol levels.  This study compared MS to Immunoassay.
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Prostate cancer risk in testoster... [J Steroid Biochem Mol Biol. 2006] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...17113983 Testosterone treatment therapy prostate prostate cancer testosterone deficiency men hormone hormones cancer
shared by Nathan Goodyear on 05 Jul 12 - No Cached
  • In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found
  • Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer
  • Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone.
  • Nathan Goodyear on 05 Jul 12
     
    testosterone therapy does not increase prostate cancer.
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Neuroprotection of Sex Steroids - 0 views

www.ncbi.nlm.nih.gov/...PMC3036837 hormones estrogen progesterone testosterone sex hormones brain neurology neuroprotection neuroprotective hormones hormone
shared by Nathan Goodyear on 10 Jul 12 - No Cached
  • Nathan Goodyear on 10 Jul 12
     
    great article on sex hormones and neuroprotection.  This article summarizes the research on estrogen, progesterone, and aromatase activity in in vitro and in vivo studies.  Additionally, the study reviews the androgenic neuroprotection in men.  Who has said that hormones are not needed post menopausal again?  Maybe, that is the sign that they need the neuroprotective effect of hormones.
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Transport of steroid hormones: bindi... [J Clin Endocrinol Metab. 1981] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...7195404 testosterone saliva salivary hormone hormones aromatase SHBG estrogen men male
shared by Nathan Goodyear on 28 Aug 12 - No Cached
  • Nathan Goodyear on 28 Aug 12
     
    Increased aromatase activity in men increases testosterone to estrogen production, which causes increase in SHBG and thus a reduction in the bioavailability of free testosterone.  
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Saliva collection devices affect sex steroid ... [Clin Chim Acta. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...22579929 saliva collection Salivette salivary hormone hormones
shared by Nathan Goodyear on 14 Aug 12 - No Cached
  • Nathan Goodyear on 14 Aug 12
     
    This study suggests that "salivette" devices alter saliva hormone concentrations.  Salivette's are usually cotton rolls in saliva tubes.  At Seasons, we do not use the Salivette rolls.
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Adiponectin is involved in the protective effect of... [Steroids. 2008] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...18534650 DHEA adiponectin overweight obesity omega-6 omega-3 n-6 n-3
shared by Nathan Goodyear on 01 Mar 12 - No Cached
  • Nathan Goodyear on 01 Mar 12
     
    DHEA increased adiponectin, improved omega 6/omega 3 ratios, and improved body fat content.
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Challenges and benefits of endogenous steroid an... [Bioanalysis. 2011] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...22122603 saliva salivary testing hormone hormones LC-MS_MS mass spectroscopy GC-MS
shared by Nathan Goodyear on 05 Jun 12 - No Cached
  • Nathan Goodyear on 05 Jun 12
     
    LC-MS/MS shown to be "accurate and highly sensitive" when compared to GC-MS for saliva testing of hormones.  Up to this point, GC-MS has been considered the "gold standard".
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Sex steroids and cardiovascular disease Yeap BB - Asian J Androl - 0 views

www.ajandrology.com/article.asp cardiovascular disease CVD sex estradiol carotid intima-media thickness hormones hormone men Testosterone estrogen
shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • Levels of SHBG are higher in older men, therefore levels of free T decline more steeply than total T as men's age increases.
  • calculations based on mass action equations may not reflect precisely free T measured using a reference method
  • free T declines more steeply with age than total T in both cross-sectional [35] and longitudinal studies, [36] as does free E2 in comparison to total E2
  • ...22 more annotations...
  • T may slow development of or progression of atherosclerosis by modulating effects on insulin resistance, inflammation, endothelial function, preclinical atherosclerosis or the vasculature.
  • these cross-sectional and longitudinal studies support a relationship between low circulating T with CIMT and higher E2 with its progression
  • lower levels of T are biomarkers for aortic vascular disease
  • circulating free T was negatively associated with the presence of AAA
  • luteinizing hormone (LH) was positively associated.
  • low levels of total or bioavailable T were associated with aortic atherosclerosis manifested as calcified deposits detected by radiography
  • Men with total or free T in the lowest quartile had increased adjusted ORs for PAD defined as ABI <0.90, as did men with free E2 in the highest quartile of values
  • The apparent association of SHBG with intermittent claudication reflects the correlation of total T with SHBG, while the contribution of E2 to risk of PAD remains unclear
  • men with total T in the lowest quartile of values (<11.7 nmol l−1 ) experienced an increased incidence of stroke or transient ischemic attack
  • lower total T with increased incidence of CVD events
  • cohort studies in mostly older men have supported the association of lower androgen levels with higher mortality
  • lower total or free T levels were associated with mortality in older men, but with discordant results for cause-specific mortality and for associations of E2
  • several large studies identifying lower endogenous levels of total or free T as independent predictors of all-cause or CVD-related deaths in middle-aged and older men
  • T exhibits anti-inflammatory effects, enhances flow-mediated brachial artery reactivity, and reduces arterial stiffness
  • Short-term T therapy had a beneficial effect on exercise-induced myocardial ischemia in middle-aged men with coronary artery disease or chronic stable angina, [95],[96],[97] and reduced angina frequency in older men with diabetes and coronary artery disease
  • T therapy resulted in an increase in treadmill test duration and time to ST segment depression
  • there are interventional studies supporting a protective effect of exogenous T against myocardial ischemia in men with coronary artery disease
  • employ conservative doses
    • Nathan Goodyear
      Nathan Goodyear on 16 Jan 14
       
      This dosing is 100 fold higher then peak production of a  young man at 20-22.
  • Observational studies indicate that lower levels of endogenous T in older men are associated with the presence of carotid atherosclerosis, aortic and peripheral vascular disease, and incidence of CVD events and mortality
  • Interventional studies have shown beneficial effects of exogenous T on vascular function and on exercise-induced myocardial ischemia in men with coronary artery disease
    • Nathan Goodyear
      Nathan Goodyear on 16 Jan 14
       
      the therapies employed in these studies were massively overdosed.
  • Nathan Goodyear on 15 Jan 14
     
    Nice review of all the sex hormones and their relationship to CVD in men.  
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Lowered testosterone in male obesity: Mechanisms, morbidity and management Tang Fui MN,... - 0 views

www.ajandrology.com/article.asp Testosterone male obesity overweight men hormone hormones low T Low T
shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • The number of overweight people is expected to increase from 937 million in 2005 to 1.35 billion in 2030
  • Similarly the number of obese people is projected to increase from 396 million in 2005 to 573 million in 2030
  • By 2030, China alone is predicted to have more overweight men and women than the traditional market economies combined
  • ...37 more annotations...
  • diacylglycerol O-acyltransferase 2 (DGAT2), mechanistically implicated in this differential storage, [10] is regulated by dihydrotestosterone, [11] suggesting a potential role for androgens to influence the genetic predisposition to either the MHO or MONW phenotype.
  • bariatric surgery achieves 10%-30% long-term weight loss in controlled studies
  • The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years
  • Reductions in testosterone levels correlate with the severity of obesity and men
  • epidemiological data suggest that the single most powerful predictor of low testosterone is obesity, and that obesity is a major contributor of the age-associated decline in testosterone levels.
  • healthy ageing by itself is uncommonly associated with marked reductions in testosterone levels
  • obesity blunts this LH rise, obesity leads to hypothalamic-pituitary suppression irrespective of age which cannot be compensated for by physiological mechanisms
  • Reductions in total testosterone levels are largely a consequence of reductions in sex hormone binding globulin (SHBG) due to obesity-associated hyperinsulinemia
  • although controversial, measurement of free testosterone levels may provide a more accurate assessment of androgen status than the (usually preferred) measurement of total testosterone in situations where SHBG levels are outside the reference range
  • SHBG increases with age
  • marked obesity however is associated with an unequivocal reduction of free testosterone levels, where LH and follicle stimulating hormone (FSH) levels are usually low or inappropriately normal, suggesting that the dominant suppression occurs at the hypothalamic-pituitary level
  • adipose tissue, especially when in the inflamed, insulin-resistant state, expresses aromatase which converts testosterone to estradiol (E 2 ). Adipose E 2 in turn may feedback negatively to decrease pituitary gonadotropin secretion
  • diabetic obesity is associated with decreases in circulatory E 2
  • In addition to E 2 , increased visceral fat also releases increased amounts of pro-inflammatory cytokines, insulin and leptin; all of which may inhibit the activity of the HPT axis at multiple levels
  • In the prospective Massachusetts Male Aging Study (MMAS), moving from a non-obese to an obese state resulted in a decline of testosterone levels
  • weight loss, whether by diet or surgery, increases testosterone levels proportional to the amount of weight lost
  • fat is androgen-responsive
  • low testosterone may augment the effects of a hypercaloric diet
  • In human male ex vivo adipose tissue, testosterone decreased adipocyte differentiation by 50%.
  • Testosterone enhances catecholamine-induced lipolysis in vitro and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo
  • in men with prostate cancer receiving 12 months of androgen deprivation therapy, fat mass increased by 3.4 kg and abdominal VAT by 22%, with the majority of these changes established within 6 months
  • severe sex steroid deficiency can increase fat mass rapidly
  • bidirectional relationship between testosterone and obesity
  • increasing body fat suppresses the HPT axis by multiple mechanisms [30] via increased secretion of pro-inflammatory cytokines, insulin resistance and diabetes; [19],[44] while on the other hand low testosterone promotes further accumulation of total and visceral fat mass, thereby exacerbating the gonadotropin inhibition
  • androgens may play a more significant role in VAT than SAT
  • men undergoing androgen depletion for prostate cancer show more marked increases in visceral compared to subcutaneous fat following treatment
    • Nathan Goodyear
      Nathan Goodyear on 16 Jan 14
       
      Interesting: low T increases VAT, yet T therapy does not reduce VAT, yet T therapy reduces SAT.
  • irisin, derived from muscle, induces brown fat-like properties in rodent white fat
  • androgens can act via the PPARg-pathway [37] which is implicated in the differentiation of precursor fat cells to the energy-consuming phenotype
  • low testosterone may compound the effect of increasing fat mass by making it more difficult for obese men to lose weight via exercise
  • pro-inflammatory cytokines released by adipose tissue may contribute to loss of muscle mass and function, leading to inactivity and further weight gain in a vicious cycle
  • Sarcopenic obesity, a phenotype recapitulated in men receiving ADT for prostate cancer, [55] may not only be associated with functional limitations, but also aggravate the metabolic risks of obesity;
  • observational evidence associating higher endogenous testosterone with reduced loss of muscle mass and crude measures of muscle function in men losing weight
  • genuine reactivation of the HPT axis in obese men requires more substantial weight-loss
  • A number of intervention studies have confirmed that both diet- and surgically-induced weight losses are associated with increased testosterone, with the rise in testosterone generally proportional to the amount of weight lost
  • men, regardless of obesity level, can benefit from the effect of weight loss.
  • inconsistent effect of testosterone on VAT
  • Nathan Goodyear on 15 Jan 14
     
    to be read
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Studies on the Progesterone Receptor Content and Steroid Metabolism in Normal and Patho... - 0 views

press.endocrine.org/...jcem-48-4-585 progesterone metabolite metabolites 5-alpha pregnenes hormone hormones metabolism women 4-pregnene 5-alpha pregnene 4-pregnenes breast cancer
shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • Nathan Goodyear on 27 Jan 14
     
    One of the first studies to document progesterone metabolites in breast tissue.
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Acute Sex Steroid Withdrawal Reduces Insulin Sensitivity in Healthy Men with Idiopathic... - 0 views

press.endocrine.org/...jc.2007-0454 Low t Testosterone insulin sensitivity resistance men male hormone inflammation glucose
shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Nathan Goodyear on 04 Feb 14
     
    This study looked at a small number of men with low T.  Therapy was abruptly stopped and the effects were followed.  Insulin function declined.  There was a trend to increased glucose and IL-6.
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Membrane 5alpha-pregnane-3,20-dio... [J Steroid Biochem Mol Biol. 2005] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...16154741 progesterone metabolite metabolites 3-alpha pregnene 3-alpha pregnenes 5-alpha pregnene 5-alpha pregnenes estradiol hormone hormones breast cancer
shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites are present on the membrane of ER/PR + as well as ER/PR - breast cancer cell lines.  The balance of 5 alpha pregnane:3 alpha pregnane regulates tumor genesis.  Estradiol increased 5 alpha pregnane receptors as well as 5 alpha pregnane unregulated itself via autocrine activity.  The 3 alpha pregnenes, 3 alpha hydroxyprogesterone and 20 alpha-dihydroprogesterone, decrease the 5 alpha pregnane receptors via paracrine activity.
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Regulation of estrogen re... [J Steroid Biochem Mol Biol. 2007 Nov-Dec] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...17683929 progesterone metabolite metabolites ER estrogen receptors hormone hormones
shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    In vitro study finds that progesterone metabolites effect expression of estrogen receptors.  The progesterone metabolite 5alphaP increased ER alpha expression.  This is important as ER alpha promotes growth and inflammation.
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Testosterone and glucose metabolism in men: current concepts and controversies - 0 views

joe.endocrinology-journals.org/...R37.full Low T Testosterone metabolic syndrome MetS Diabetes men male glucose hormone hormones g
shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges based on healthy young men
  • The absence of high-level evidence in this area is illustrated by the Endocrine Society testosterone therapy in men with androgen deficiency clinical practice guidelines (Bhasin et al. 2010), which are appropriate for, but not specific to men with metabolic disorders. All 32 recommendations made in these guidelines are based on either very low or low quality evidence.
  • A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
  • ...59 more annotations...
  • The presence of symptoms was more closely linked to increasing age than to testosterone levels
  • Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone
  • low testosterone is more predictive of the metabolic syndrome in lean men
  • Cross-sectional studies uniformly show that 30–50% of men with type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men
  • In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.
  • both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable with the effect of 10 years of ageing
  • In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia
  • In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      probably the most important point made in this article
  • low testosterone identifies men with an adverse metabolic phenotype
  • Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant
  • increased inflammation, evidenced by higher CRP levels
  • Bioavailable but not free testosterone was independently predictive of mortality
  • It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.
  • In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone compared with total testosterone
  • In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome
  • low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
  • In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control
  • SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids
  • In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      expensive, laborious process filled with variables
  • Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.
  • Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.
  • testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
  • testosterone regulates the metabolic functions of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.
  • Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.
  • More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
  • Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.
  • There is also evidence that testosterone regulates insulin sensitivity directly and acutely
  • In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months
  • More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies
  • Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.
  • the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.
  • Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the age-related decline in testosterone levels
  • there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone
  • Circulating testosterone, on an average 30%, is lower in obese compared with lean men
  • increased visceral fat is an important component in the association of low testosterone and insulin resistance
  • The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels
  • obesity is a dominant risk factor
  • men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty
  • Only 5% of men with type 2 diabetes have elevated LH levels
  • inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
  • Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion from GNRH neurons situated in the preoptic area
  • kisspeptin has emerged as one of the most potent secretagogues of GNRH release
  • hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
  • A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects
  • suppression of the diabesity-associated HPT axis is functional, and may hence be reversible
  • Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
  • weight gain and development of diabetes accelerate the age-related decline in testosterone
  • Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone
  • 55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up, suggesting that androgen deficiency is not a stable state
  • Weight loss can reactivate the hypothalamic–pituitary–testicular axis
  • Leptin treatment resolves hypogonadism in leptin-deficient men
  • The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
  • Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
  • change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).
  • weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
  • There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
  • in men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased
  • testosterone levels should be measured after successful weight loss to identify men with an insufficient rise in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate evaluation and management.
  • Nathan Goodyear on 04 Feb 14
     
    Article discusses the expanding evidence of low T and Metabolic syndrome.
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Roles of the gonadal steroid hormones in psychiatric depression in men and women - Rese... - 0 views

www.researchgate.net/...ic_depression_in_men_and_women depression estradiol estrogen men Testosterone women hormones hormone
shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Nathan Goodyear on 03 Feb 14
     
    Fascinating difference in the sexes.  High estradiol is found to be associated with depression in men and high Testosterone is found to be associated with depression in women.  The exact mechanism or strength of association is unstated.
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Progesterone metabolites regulate induction, growth, and suppression of estrogen- and p... - 0 views

www.ncbi.nlm.nih.gov/...PMC3706910 progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen
shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
  • Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
  • When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
  • ...31 more annotations...
  • Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
  • Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
  • The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
  • hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
  • a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
  • about 90% of normal proliferating breast epithelial cells are receptor negative
  • Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
  • The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
  • In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
  • the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
  • Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
  • The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
  • The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
  • In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
  • When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
  • The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
  • Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
  • ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
  • 3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
  • serum from mice with tumors had significantly more 5αP than 3αHP
  • the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
  • Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
  • Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
  • breast carcinomas are able to synthesize progesterone
  • The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
  • Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
  • 5α-reductase and 5αPR levels are upregulated by 5αP
  • in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
  • the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
  • because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
  • The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites and breast cancer
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